Safety of COVID-19 Vaccine in Patients with Rheumatic and Musculoskeletal Diseases

Objectives: The main purpose of this study was to determine the frequency of COVID-19 vaccine side effects in patients with rheumatic diseases and to examine any potential associations with medications, disease type, or comorbidities. Methods: A multicentre cross-sectional study from rheumatology units in different hospitals in Iraq was carried out between 8th of August 2021 and 4th of August 2022. Patients were eligible for inclusion if they have a rheumatic disease and have taken one or more doses of any COVID-19 vaccine. Results: A total of 661 (57.8% female, mean age 46.51± 12.97 years) patients with rheumatic illnesses who received the “COVID-19” vaccination were included in this study. Rheumatoid arthritis was the most frequent diagnostic group. The Pfizer vaccine was given to the majority of patients (74.6%), followed by Sinopharm (16.2%), and AstraZeneca (9.2%). Side effects were detected in 661(100%) and 528 (100%) patients following the first and second vaccination doses, respectively; among which the most frequent were injection site pain in 57.8% following the first dose and 47.6% after the second dose, followed by fatigue and fever. According to multivariate logistic regression models, age (B=−0.204, p = 0.000), had a significantly inverse correlation coefficient with the experience of greater side effects. Rheumatic disease flares reported in 9.9%, 10.3%, and 8.2% of patients who received the Pfizer, Sinopharm, and AstraZeneca vaccines, respectively. Conclusion: The “COVID-19” vaccination has a reassuring safety profile with no greater risk of adverse events in any specific illness or pharmacological therapy.


INTRODUCTION
Since December 2019, the "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)" has emerged as a serious global health emergency, infecting over 81 million people and killing over one million, causing global health and economic challenges and forcing the entire world to follow strict isolation protocols. 1any observational studies have segregated risk factors for mortality in COVID-19 infection and consistently, immunosuppression stands out as a well-identified risk.Increased mortality was found in patients with lupus, rheumatoid arthritis (RA), and psoriatic arthritis, compared to those having no rheumatic diseases with an adjusted odds ratio [aOR] of 1.30.In addition, patients with rheumatic disorders were more likely to be hospitalised, especially those receiving large doses of glucocorticoids (≥10 mg/day), with an odd ratio of 2.09. 2 It has been also demonstrated that mycophenolate mofetil and rituximab are significantly linked to worse outcomes after SARS-CoV-2 infection. 3accination is efficacious in limiting transmission, morbidity, and mortality.However, the COVID-19 vaccination is infamous due to the combined causes of public misinformation, post-vaccination reports of adverse effects, and scepticism related to the short production period. 4t is critical to address anti-vaccine concerns in order to improve vaccination rates and achieve protection for patients with rheumatic disease who are hesitant to receive vaccination due to side effect concerns. 5our vaccines were registered in Iraq, but only three were eventually purchased by the government, namely: Pfizer/ BioNTech, Gamaleya, Oxford/AstraZeneca Vaxzevria, and Sinopharm (Beijing). 6As there is a lack of information addressing patient fears and vaccination adverse events in Iraqi patients with rheumatic diseases, this study aimed to gather information regarding the frequency of COVID-19 vaccine side effects in Iraqi patients with rheumatic diseases and to look for any possible relationships with drugs, disease type, or comorbid illnesses.

Study design and settings
A multicentre, "cross-sectional" observational study was carried out at the rheumatology clinics in 7 tertiary hospitals providing care for patients with rheumatic diseases in Iraq during the period from August 8 th , 2021, until August 4 th , 2022.Consecutive patients receiving follow-up care in these rheumatology clinics were recruited.Data was collected by the practicing physicians and postgraduate Rheumatology students through structured interview conducted face-to-face.Generally speaking, patients with rheumatic diseases routinely underwent a face-to-face evaluation before receiving the COVID vaccine.Patients were asked to report any adverse event either via telephone or by attending to the clinic.Patients with suspected disease reactivation underwent a face-to-face evaluation in order to confirm the flare and record the associated characteristics.Participants Any patient with mechanical or inflammatory rheumatic disease aged ≥18 years who received at least one dose of any of the three available COVID vaccines was included in the study.No patient had received a booster dose during the study period.

Data collection
A questionnaire was constructed to gather the following data through direct interview, in addition to the information available in patients records: Age, gender, disease type, disease activity state at the time of immunisation, drugs used at the time of vaccination, use and dose of steroids, if any, and history of COVID infection prior to vaccination.Data regarding the type of vaccine, number of doses, COVID infection after vaccination, and if positive, the duration between vaccination and infection, and the sequelae of infection; disease status after vaccination; any adverse events after receiving the vaccine, and the need for medical interference for the adverse events, if any were also included.

Statistical Analysis
The information was extracted to an Excel sheet and managed by the Statistical Package for Social Sciences version 26 SPSS 26 software.Continuous variables were expressed in mean±standard deviation (SD).Categorical variables were expressed as numbers and percentages; the duration was expressed in median and range.To assess possible predictors of adverse reaction to vaccination, multivariate logistic regression analysis was used with a statistical significance set to a p-value of less than 0.05.AstraZeneca vaccine, the flare developed in 6 patients (8.2%) with a median interval of 7.5 days and was in the form of arthralgia 4(6.6%), fatigue 2(3.3%), and arthritis 1(1.6%).The difference among the study groups regarding the disease flare after the vaccinations is statistically insignificant (p=0.993).All the flares occurred in patients with inflammatory rheumatic diseases.Side effects were detected in 661(100%) and 528 (100%) patients following the first and second vaccination doses, respectively.Most of the side effects for all COVID-19 vaccines included in the study, whether the 1 st or 2 nd dose, developed within day zero and subsequent days 1 and 2, as shown in Table 5.Table 6 demonstrates the side effects experienced from COVID-19 vaccine and shows that the most frequently detected side effect was pain at site of injection which developed in 382(57.8%)after the first dose and    8).

DISCUSSION
An increased risk of developing severe COVID-19 infections has been evidenced in rheumatic disease patients, and COVID-19 vaccination is strictly recommended for these patients.Data on the safety and effectiveness of COVID-19 vaccines in people with rheumatic disorders, however, are still inconclusive.An issue that is becoming more crucial is the potential emergence of adverse events, including flare-up of the underlying rheumatic disease.This study investigated the safety of three different types of "COVID-19" vaccines among Iraqi patients with rheumatic disorders and reported that the SARS-CoV-2 vaccinations' safety profile in this cohort was reassuring.The vast majority of patients responded favourably to their vaccine, and flare-ups of rheumatic disorders were quite uncommon for all types of vaccines with a median interval of 4-7.5 days post vaccination.The majority of flare manifested as arthritis, arthralgia, and fatigue, with very rare reports of neuro-psychiatric and renal flares (0.2%).Most side effects related to vaccines were mild, involving temporary local and systemic symptoms with only (4.4%, 0.3%, 0.3%) requiring medical consultation, emergency consultation, and hospital admission respectively.In terms of flares, our data suggested that the risk of rheumatic diseases flare after vaccination is low and not substantially associated with any specific type of vaccine, with the observed percentages being consistent with other observational studies that have documented the flare rate of rheumatic diseases after COVID-19 vaccination, ranging from 0.4% to 20%,  and in agreement with the findings of a meta-analysis of these studies that found comparable flare rates of rheumatic disease after "mRNA" vaccination and " adenovirus"-based vaccination, which were 7% (,5%-9%; P=0.000) and 8% (4%-12%; P=0.000), respectively. 29Similar to the results of our study, the majority of flares developed soon after receiving the COVID-19 immunisation and consistently occurred within the first week.Visentini et al. also obtained similar results, as 83% of the flare occurred within seven days.11 Concerning flare severity, most of the flares after "COVID-19" vaccination were related mainly to musculoskeletal and cutaneous manifestations, and this finding was confirmed by multiple studies that demonstrated that the flare-up of rheumatic illnesses following COVID-19 immunization primarily manifested as joint pain, stiffness, and swelling, particularly for inflammatory arthritis.7,8,10,12,17,18,22,23 Regarding SLE, in addition to arthritis, cutaneous and mucosal manifestations, such as malar erythema and alopecia, were also frequent.7,11,13,17 Additionally, fatigue and myalgia are frequently experienced by flare sufferers.12,[16][17][18] Furthermore, other studies investigated disease activity before and after immunisation and discovered no discernible difference in the overall disease activity of rheumatic diseases, so indirectly demonstrating an insignificant flare-up.14,25,30,31 Regarding vaccination side effects, the frequency and type of side effects were similar between vaccines, with the possible exception of a slightly greater frequency of discomfort at the injection site with the Pfizer vaccine and fatigue with the AstraZeneca vaccine.The adverse effect data are consistent with earlier studies in rheumatic illnesses patients.12,17,22,[32][33][34][35] We underline that thrombocytopenia events were not reported in our study population.

Table 1 .
Baseline demographic and clinical characteristics of the study sample.

Disease Activity at time of vaccination
prevalent rheumatic disease (30.6%), followed by non-inflammatory/ mechanical rheumatic and musculoskeletal diseases (RMDs) (23.6%) and Axial spondyloarthritis (SpA) (22.1%), while the other types represent 23.7% as shown in Table1.The majority of the patients (85.2%) were in remission or low disease activity at the time of vaccination (Table1).Table2demonstrates the types of COVID-19 vaccine received among rheumatic disease patients and shows that 493 (74.6%) out of the sample took Pfizer vaccine; 294 (44.5%) were females and 199 (30.1%) were males; most of them received 2 doses.Sinopharm vaccine had been taken by 107 (16.2%) of the study sample; the majority of them received 2 doses.AstraZeneca vaccine had been taken by 61 (9.2%) patients; most of them received 2 doses of vaccine.

Table 3
demonstrates the COVID-19 infection after vaccination and shows that the COVID-19 infection occurred in 8 patients after the first dose; 6 out of the 8 were after the Pfizer vaccine and 2 were found after the Sinopharm vaccine; and 22 patients after the second dose; 14 after the Pfizer vaccine, 4 after the Sinopharm vaccine, and 4 after the AstraZeneca vaccine.The median duration of infection after the first Pfizer dose is 9 days, and it is 50 days after receiving the second dose.TNF-α: tumour necrosis factor alpha; NSAIDs: non-steroidal anti-inflammatory drugs; RMDs: rheumatic and musculoskeletal diseases; SpA: spondyloarthritis; SLE: systemic lupus erythematosus; PsA: psoriatic arthritis.

Table 1 .
Baseline demographic and clinical characteristics of the study sample.

Table 2 .
Types of COVID-19 vaccine received among rheumatic disease patients.

Table 4 .
Type of rheumatic diseases flare among vaccinated patients.

Table 5 .
Timing of onset of side-effects after COVID-19 vaccines, days.

Table 7 .
Need for consultations or hospital admission for side-effects.
37It should be noted that the studies' methodology varied greatly and that this was an indirect comparison of the vaccines.Although evaluating the outcome of post vaccination COVID-19 infection was not the primary objective of this study, it was found that

Table 8 .
Multivariate logistic regression analysis on factors associated with experiencing side effects of the vaccine.81%were treated at home, two patients required hospitalisation without O2, and three patients required O2, but only one patient needed ICU admission.These findings, however, are insufficient to conclude that one vaccine is more effective than another for protecting against COVID-19 infection in those with rheumatic illnesses.This study was the first to give a descriptive analysis and assessment of contributing factors and adverse effects of the COVID-19 vaccine in Iraqi patients with rheumatic illnesses.The sample size is a significant drawback, and the lack of a control group made it impossible to compare the patient's symptoms and side effects to those of people with similar conditions or the general population; and patient self-reported symptoms and side effects were at risk of recall bias.In conclusion, our findings present an encouraging picture regarding the safety of "COVID-19" vaccination in patients with rheumatic disorders.Almost all the reported side effects were mild to moderate.Reassuringly, no serious flare up of underlying rheumatic disorder was documented after vaccination.These data need to be disseminated to reduce vaccine hesitancy in patients with rheumatic diseases.